This invention relates to a process for the preparation of 3,5-diaminobenzotrifluoride by the reduction of 4-chloro-3,5-dinitrobenzotrifluoride using hydrogen as a reducing agent in the presence of palladium on carbon as a catalyst. Since 4-chloro-3,5-diaminobenzotrifluoride is difficult to separate from 3,5-diaminobenzotrifluoride itself, it is a particular object of the present invention to provide a process which produces 3,5-diaminobenzotrifluoride without significant production of 4-chloro-3,5-diaminobenzotrifluoride.
The reduction of aromatic nitro compounds containing halogen on the aromatic ring is unpredictable. Hydrogenation using a palladium on carbon catalyst generally reduces the nitro group to an amine. However, the hydrogenation has been reported to fail in some cases. In addition, the effects of such hydrogenation upon a ring halogen are unpredictable. Occasionally the ring halogen is removed from the ring and replaced by a hydrogen. However, in many cases the hydrogenation leaves the ring halogen intact.
A. Weizmann discloses in J. Am. Chem. Soc., 71, 4154 (1949), that the catalytic hydrogenation of diethyl aminoethyl 4-nitro-2-chlorobenzoate using palladium on barium sulfate as a catalyst was impractical from a preparative point of view. The nitro compound was often incompletely reduced. The chlorine was occasionally removed from the ring while in other reactions it remained on the ring. Similar hydrogenation experiments conducted with 4-nitro-2-chlorobenzoic acid and its ethyl ester, using palladium on barium sulfate as a catalyst, produced variable results depending upon the solvent employed. In ethyl acetate, the reduction proceeded with retention of the chlorine. In this solvent, the acid and the ethyl ester gave quantitative yields of 4-amino-2-chlorobenzoic acid and ethyl 4-amino-2-chlorobenzoate, respectively. In isopropyl alcohol, the 4-nitro-2-chlorobenzoic acid and its ethyl ester were reduced to 4-aminobenzoic acid and its ethyl ester, respectively. In other words, in isopropyl alcohol the chlorine was removed in the reduction process. An aqueous solution of sodium 4-nitro-2-chlorobenzoate yielded, on workup, 4-aminobenzoic acid.
Bouchet et al. disclose in Syn. Commun., 4, 57-9 (1974), as cited in CA 81:25598m, that paranitrochlorobenzene may be reduced to parachloroaniline using hydrogen in the presence of a palladium on carbon catalyst in an aqueous alcohol solvent buffered to pH 7.
Ovchinnikov et al. (in Prikl. Hkim., (62), 37-44 (1969)) disclosed that meta and para chloronitrobenzenes may be hydrogenated to meta and parachloroanilines, respectively, using hydrogen gas and a 2% palladium on carbon catalyst. Approximately 2% dehalogenation was observed. It was also observed that the amount of dehalogenation was related to the type of carbon used as the catalyst carrier and depended upon the height of the catalyst bed.
U.S. Pat. No. 3,666,813 discloses that aromatic haloamines can be prepared by hydrogenating the corresponding chloro-nitro aromatic compound in the presence of a modified palladium on charcoal catalyst. The palladium on carbon catalyst is modified by treating it with a solution of a bismuth, lead, or silver salt.
U.S. Pat. No. 3,073,865 discloses a process for catalytically reducing halogen-substituted aromatic nitro compounds to the corresponding amines. The process is designed to reduce the aromatic nitro compound without removing the ring-halogens. The inventor discloses that magnesium oxide at levels between 0.1 and 1% by weight of nitro compound being reduced tends to prevent dehalogenation. At higher levels of magnesium oxide, magnesium oxide tends to promote dehalogenation. However, the examples provided in the patent show that in cases where the process did not produce the desired retention of the halogen atom, dehalogenation occurred to the extent of approximately 40%. In one case, a dechlorination of 80% occurred.
C. Paal and Christian Muller-Lobeck, Ber. 64b 2142-50 (1931), (as cited in CA 26 pp. 85 and 86) studied the hydrogenation of .alpha. and .beta.-chloro butyric acid, .alpha. and .beta.-chloro proprionic acid, and .alpha. and .beta.-chloro ethyl benzene. In each case, the .alpha.-chloro molecule more readily reacts with hydrogen to remove the chlorine than does the .beta.-chloro isomer. The catalyst employed for the reaction was palladium. The authors also observed that magnesium oxide promoted the reaction by reacting with the HCl released. In the absence of a base to absorb the HCl, the liberated acid prevents further hydrogenation.
European Patent Application EP 88667 (as abstracted in Chem. Abstracts 100:52475m and Derwent accession #C83-089930) discloses that chlorinated or brominated methylenedianilines can be prepared by the nitration and reduction of the corresponding aromatic halides. The reduction is carried out in methanol solvent with hydrogen gas in the presence of 5% palladium on carbon as a catalyst. The aromatic halide is retained during reduction.
Chakrabarti et al. disclose in two papers (J. Med. Chem. 23 pp. 878 and 884 (1980)) a multi-step reduction and cyclization reaction in which the first step is a hydrogenation using 10% palladium on carbon as a catalyst. The solvent was a mixture of ethanol and ethyl acetate. The molecules that are subjected to hydrogenation are substituted nitrobenzenes with a halogen at the 3 position and a substituted amino group at the 6 position. In one paper, the compound studied has fluorine as the halogen and in the other the halogen is chlorine. In each case, the nitro group was reduced to the amine while the halogen was not attacked.
Japanese Patent 63/010739 (as abstracted in Chem. Abstracts 109:92449y) discloses that chloro-fluoro-benzotrifluoride derivatives can be dechlorinated using hydrogen gas and 5% palladium charcoal catalysts in a methanol solvent. The ring chlorines are preferentially removed over the ring fluorines. Apparently no base was used in this process. Comparative Example 9 illustrates that a base is required to reduce the compound of the Applicant's process.
Vergnani et al. disclosed in Helv. Chim. Acta, 68, 1828, (1985), that 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline undergoes simultaneous removal of the aromatic bromine and reduction of the nitro group to an amine when treated with hydrogen gas in the presence of a 10% palladium on charcoal catalyst and triethylamine using methanol as a solvent.
Japanese Patent 58157749 (as abstracted in Chem. Abstracts 100:51247b) discloses that 2,2',4-trichloro-4',5-dinitrodiphenyl ether may be hydrogenated in the presence of 5% palladium on carbon catalyst in methanol to form 3,4'-diaminodiphenyl ether.
The substance that is reduced using the process of this invention, that is, 4-chloro-3,5-dinitrobenzotrifluoride, is a rather reactive molecule and can undergo side reactions during any reduction process. Crampton and Greenhalgh have disclosed in J. Chem. Soc., Perkins Transaction II, p. 187 (1986), that 4-chloro-3,5-dinitrobenzotrifluoride is subject to nucleophyllic attack on the chlorine. Thus, hydroxide ion can displace the chlorine to yield 4-hydroxy-3,5-dinitrobenzotrifluoride.
European Patent 038,465 discloses the reduction of 2-trifluoromethyl-4-chloronitrobenzene to 2-trifluoromethylaniline in a single step using hydrogen gas in a polar medium. The preferred solvent is water and/or a 1-3 carbon alcohol, especially methanol, and the preferred bases are alkali hydroxides, ammonia, or lower aliphatic amines. Attempts were made in our laboratory to reduce 4-chloro-3,5-dinitrobenzotrifluoride using the method set forth in European Patent 038,465. Comparative Example 1 and 2 illustrate that the procedure of this patent does not work in the case of 4-chloro-3,5-dinitrobenzotrifluoride. If the sodium hydroxide is added as part of the initial charge, the level of impurities is extremely high. On the other hand, if the nitro groups are reduced, and then the sodium hydroxide is added, the impurity level is only 6.3%. However, the amount of 4-chloro-3,5-diaminobenzotrifluoride found is approximately 40%.